Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol-carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. In addition, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals.
There are an increasing number of patents in the literature disclosing compounds which are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued to DeVries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol. U.S. Pat. No. 4,824,843, issued to Hoefle et al. on Apr. 25, 1989, and the related U.S. Pat. No. 4,882,357, issued to Creger et al. on Nov. 21, 1989, disclose a series of substituted N-phenyl-2,2-dimethyl-5-aryloxypentanamides, which prevent the intestinal absorption of cholesterol in mammals by inhibiting ACAT. European Patent Application 325,397, filed by Ito on Jul. 26, 1989, discloses a series of compounds consisting of two N-cycloalkyl-N'-arylurea units linked at nitrogen by a dialkylphenyl unit, which are inhibitors of the ACAT enzyme. U.S. Pat. No. 4,868,210, issued to Trivedi on Sep. 19, 1989, and the related European Patent Applications 335,374 filed by Trivedi on Mar. 30, 1988, and 386,487, filed by Trivedi on Feb. 9, 1989, disclose certain N-2,6-dialkyl- or N-2,6-dialkoxyphenyl-N'arylalkyl ureas as potent inhibitors of ACAT. European Patent Application 354,994, filed by Meguro and Ikeda on Feb. 21, 1990, discloses certain N-aryl-N'-quinolin-4-yl ureas as ACAT inhibitors. European Patent Application 370,740, filed by Jackson et al. on Nov. 21, 1988, discloses ACAT inhibitors similar in composition to those of DeVries (supra).
The following references also disclose compounds which are inhibitors of ACAT useful as antihypercholesterolemic and/or antiatherosclerotic agents: U.S. Pat. No. 4,900,744; European Patent Application EP-A-372,445; International Application WO 91/09021; International Application WO 91/10662; International Application WO 91/13876; German Laid Open Application No. DE 3504679; German Laid Open Application No. DE 3504680.
European Patent Application EP 418,071 A2, filed by McCarthy et al., discloses compounds of the formula ##STR2## wherein Q is --CR.sup.2 R.sup.3 R.sup.4 or --NR.sup.17 R.sup.18 ;
R.sup.1 is ##STR3## R.sup.2, R.sup.3 and R.sup.4 may be the same or different, and
(a) are selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, A, XR.sup.10, C.sub.7 -C.sub.13 arylalkyl, C.sub.6 -C.sub.12 cycloalkylalkyl, with the proviso that at least one of R.sup.2, R.sup.3 and R.sup.4 must be A, and with the proviso that when R.sup.1 is a group of the formula XXVII or a group of the formula XXVI wherein G is nitrogen and wherein neither R.sup.5, R.sup.6 or R.sup.15 is NR.sup.19 R.sup.20, C.sub.1 -C.sub.6 alkylthio, C.sub.5 -C.sub.7 cycloalkylthio, C.sub.7 -C.sub.11 arylalkylthio, phenylthio or heteroalkylthio, either at least one of R.sup.2, R.sup.3 and R.sup.4 must be XR.sup.10, or two of R.sup.2, R.sup.3 and R.sup.4 must be A; or
(b) R.sup.2 and R.sup.3 together with the carbon to which they are attached form a cyclic or bicyclic system selected from the group consisting of C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloalkenyl, C.sub.6 -C.sub.14 bicycloalkyl, C.sub.6 -C.sub.14 bicycloalkenyl, and aryl-fused and heteroaryl-fused systems containing 8 to 15 carbon atoms, one ring of any of said aryl-fused and heteroaryl-fused systems being aromatic and the ring containing the carbon to which R.sup.2 and R.sup.3 are attached being non-aromatic, one of the carbons of said aromatic ring being optionally replaced by sulfur or oxygen, one or more carbons of said non-aromatic ring being optionally replaced by sulfur or oxygen, and one or more carbons of said aromatic ring being optionally replaced by nitrogen; one or two carbons of said cycloalkyl or bicycloalkyl groups being optionally replaced by sulfur or oxygen, and said cylic or bicyclic system being optionally substituted with one to five substituents independently selected from the group consisting of phenyl, substituted phenyl, C.sub.1 -C.sub.6 alkyl and A, with the proviso that one and only one of said substituents is A, and one and only one of said substituents is phenyl or substituted phenyl, said substituted phenyl being substituted with one or more substituents independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkylthio, halogen and trifluoromethyl; and
R.sup.4 is H, XR.sup.10 or A;
with the proviso that when R.sup.1 is a group of the formula XXVII or a group of the formula XXVI wherein G is nitrogen and wherein neither R.sup.5, R.sup.6 nor R.sup.15 is NR.sup.19 R.sup.20, C.sub.1 -C.sub.6 alkylthio, C.sub.5 -C.sub.7 cycloalkylthio, phenyl C.sub.1 -C.sub.4 alkylthio, phenylthio or heteroalkylthio, R.sup.2 and R.sup.3, together with the carbon to which they are attached, do not form a C.sub.3 -C.sub.7 cycloalkyl ring containing only carbon atoms;
A is a hydrocarbon containing 4 to 16 carbons and 0, 1 or 2 double bonds;
X is O, S, SO, SO.sub.2, NH, NR.sup.23 CO or NSO.sub.2 R.sup.24, wherein R.sup.23 is hydrogen or C.sub.1 -C.sub.6 alkyl and R.sup.24 is C.sub.1 -C.sub.6 alkyl, phenyl or C.sub.1 -C.sub.3 alkyl-phenyl;
R.sup.5, R.sup.6, R.sup.15 and R.sup.16 are each independently selected from the group consisting of hydrogen, F, Cl, I, Br, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.5 -C.sub.7 cycloalkylthio, phenyl C.sub.1 -C.sub.4 alkylthio, substituted phenylthio, heteroarylthio, heteroaryloxy, and NR.sup.19 R.sup.20, wherein R.sup.19 and R.sup.20 are the same or different and are selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, substituted phenyl, C.sub.1 -C.sub.4 acyl, aroyl, and substituted aroyl, wherein said substituted phenyl and substituted aroyl groups are substituted with one or more substituents independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogen and trifluoromethyl, or R.sup.19 and R.sup.20, together with the nitrogen to which they are attached, form a piperidine or morpholine ring; and wherein R.sup.5, R.sup.6 , R.sup.15 and R.sup.16, when attached to a bicyclic system, may be attached to either ring of such system, with the proviso that no more than 3 non-hydrogen substituents may be attached to any one ring of such system;
R.sup.7, R.sup.8 and R.sup.9 are the same or different;
R.sup.7 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, methyl and fluoro; and
R.sup.8 and R.sup.9 are each independently selected from the group consisting of C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, methyl, and fluoro;
R.sup.10 is selected from the group consisting of C.sub.4 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 straight or branched alkyl, C.sub.4 -C.sub.12 cycloalkyl-C.sub.1 -C.sub.6 alkyl, phenyl-C.sub.1 -C.sub.6 alkyl, substituted phenyl-C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkylphenyl, C.sub.1 -C.sub.6 alkyl-substituted phenyl, optionally-substituted thiazoles, optionally substituted benzothiazoles, and optionally substituted pyridines; wherein the substituents on the substituted phenyl, substituted thiazoles, substituted benzothiazoles and substituted pyridines are selected from the group consisting of C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.6 alkyl, halo and trifluoromethyl;
B, D, E and G are selected from the group consisting of nitrogen and carbon, with the proviso that one or more of B, D and E is nitrogen, and with the proviso that when G is nitrogen, the group XXVI is attached to the nitrogen of formula I at the 4 or 5 position of the pyrimidine ring (designated by a and b);
R.sup.17 and R.sup.18 are each independently selected from the group consisting of C.sub.4 -C.sub.12 straight or branched alkyl, phenyl-C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.6 alkylphenyl-C.sub.1 -C.sub.6 alkyl;
with the proviso that when Q is NR.sup.17 R.sup.18, R.sup.1 is a group of the formula XXVI or XXIV, or a group of the formula XXVII wherein R.sup.7, R.sup.8 and R.sup.9 are each methoxy.
The compounds of McCarthy et al. are disclosed as inhibitors of ACAT.
There are no known literature references disclosing the cyclic sulfide and ether compounds of this invention, their use as ACAT inhibitors, or their use to lower cholesterol or in the treatment of atherosclerosis. The invention of these compounds represents a potentially significant development in the area of treatment of atherosclerosis. The novel cyclic sulfide and ether compounds of the invention have improved potency and/or bioavailability.